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Role of dopamine D2, D4 and serotonin(2A) receptors in antipsychotic and anticataleptic action
... risperidone, sertindole and iloperidone) and MARTAs studied. Others have reported similar conclusions to our own (Seeman et al., 1997a;Seeman et al., 1997b) although the notion of higher 5-HT 2A affinity for atypical APDs persists (Langlois et al., 2012;Meltzer and Massey, 2011). Potential reasons for these discrepancies include depletion of high-affinity radioligands such as [ 3 H]-spiperone potentially leading to underestimated D 2 R tracer and therefore unlabelled compound affinities, in conjunction with differences in assay temperature and buffer salt concentration (Seeman et al., 1997a). ...
Certain atypical antipsychotic drugs (APDs) used in the treatment of schizophrenia have been hypothesized to show reduced extrapyramidal side effects (EPS), due to their ability to promote nigrostriatal dopamine release through 5-HT 2A receptor (5-HT 2A R) blockade. The strength of this hypothesis is currently limited to a consideration of the relative receptor affinities of APDs for the 5-HT 2A R and dopamine D 2 receptor (D 2 R). Here we measure the 5-HT 2A R kinetic binding properties of a series of typical and atypical APDs in a novel time-resolved fluorescence resonance energy transfer assay and correlate these properties with their observed EPS at therapeutic doses. For compounds with negligible affinity for 5-HT 2A R, EPS is robustly predicted by a D 2 R specific rebinding model that integrates D 2 R association and dissociation rates to calculate the net rate of reversal of receptor blockade ( k r ). However, we show that for compounds with significant affinity for the 5-HT 2A R, such as sertindole, higher relative 5-HT 2A occupancy over time is an indicator for a reduced propensity to cause EPS.
This study suggests that there is room for the development of novel kinetically optimised antipsychotic agents that modulate both serotonergic and dopamine function in a manner beneficial in the treatment of this chronic and debilitating disease.
... Taken together with past findings from the neuroimaging literature on the SN in both schizophrenia and eating disorders, our results suggest that enhancing the reactivity in the SN when people with AN engage in eating behaviour has the potential to be a treatment strategy. An important mechanism of action by which olanzapine and other second-generation APs may induce increases in appetite is the blockade of receptors, such as 5-hydroxytryptamine 2A , 5-hydroxytryptamine 2C serotoninergic; D 1 , D 2 , D 3 , and D 4 dopaminergic; and H 1 histaminergic, α1 and α2 adrenergic and cholinergic [25][26][27][28][29][30][31][32][33] -which are known to be involved in appetite regulation. Thus pharmacological modulation of insular reactivity through APs may increase sensitivity to food in patients with AN. ...
The salience network (SN), a set of brain regions composed of the anterior fronto-insular cortex (aFI) and the anterior cingulate cortex (ACC), is usually involved in interoception, self-regulating, and action selection. Accumulating evidence indicates that dysfunctions in this network are associated with various pathophysiological deficits in both schizophrenia and eating disorders, stemming mainly from dysfunctional information processing of internal or external stimuli. In addition, the metabolic side effects of some antipsychotics (APs), as well as their pharmacological mechanisms of action, also suggest a link between the functional and neurophysiological changes in the brain in both schizophrenia and in eating disorders. Nevertheless, there is still a knowledge gap in explicitly and directly linking the metabolic side effects associated with AP treatment with the dysfunction in SN associated with processing of food-related information in schizophrenia. Here we provide neuroimaging evidence for such a link, by presenting data on a group of schizophrenia patients who followed 16 weeks of olanzapine treatment and undertook a passive viewing task while their brain activity was recorded. In response to food-related dynamic stimuli (video clips), we observed a decreased activity in SN (aFI and ACC) after the treatment, which also correlated with ghrelin plasma concentration and a measure of dietary restraint. Taken together with past findings regarding the role of SN in both schizophrenia and eating disorders, our results suggest that enhancing the reactivity in the SN has the potential to be a treatment strategy in people with anorexia nervosa. Clinical Trial Registration Number: NCT 00290121 W W W Réseau de salience et olanzapine dans la schizophrénie : implications pour le traitement de l'anorexie mentale Le réseau de la salience (RS), un ensemble de régions cérébrales formé du cortex fronto-insulaire antérieur (FIa) et du cortex cingulaire antérieur (CCA), est habituellement impliqué dans l'intéroception, l'autorégulation, et la sélection d'actions. Les données probantes qui s'accumulent indiquent que les dysfonctions de ce réseau sont associées avec divers déficits pathophysiologiques dans la schizophrénie et les troubles alimentaires, émanant principalement du traitement dysfonctionnel de l'information des stimuli internes et externes. En outre, les effets secondaires métaboliques de certains antipsychotiques (AP), ainsi que leurs mécanismes d'action pharmacologiques suggèrent aussi un lien entre les changements fonctionnels et neurophysiologiques du cerveau dans la schizophrénie et les troubles alimentaires. Néanmoins, les connaissances ne suffisent pas encore à lier explicitement et directement les effets secondaires métaboliques associés au traitement par AP avec la dysfonction du RS associée au traitement de l'information liée aux aliments dans la schizophrénie. Nous offrons ici des preuves en neuroimagerie de ce lien, en présentent des données d'un groupe de patients souffrant de schizophrénie qui ont suivi un traitement de 16 semaines par olanzapine et qui ont effectué une tâche de visualisation passive pendant que leur activité cérébrale était enregistrée. En réponse aux stimuli dynamiques liés aux aliments (vidéoclips), nous avons observé une activité réduite du RS (FIa et CCA) après le traitement, qui corrélait aussi avec la concentration plasmatique de ghréline et une mesure des restrictions alimentaires. Pris conjointement avec les constatations passées sur le rôle du RS dans la schizophrénie et les troubles alimentaires, nos résultats suggèrent qu'accroître la réactivité du RS pourrait être une stratégie de traitement chez les personnes souffrant d'anorexie mentale. Numéro d'enregistrement d'essai clinique : NCT 00290121 open access
... Theoretically, an important candidate mechanism for olanzapine and other second-generation antipsychotics (SGA)-induced increases in appetite is the blockade of receptors such as 5-HT2A, 5-HT2C serotonergic; D1, D2, D3 and D4 dopaminergic; H1 histaminergic, a1-and a2adrenergic and cholinergic [50][51][52][53][54][55][56][57][58] involved in appetite regulation. Some clinical trials implicate the polymorphism of the 5-HT2C receptor gene in weight gain in response to SGAs. ...
There is evidence that some atypical antipsychotics, including olanzapine, can produce unwanted metabolic side effects, weight gain and diabetes. However, neuronal correlates of change related to food information processing have not been investigated with these medications. We studied the effect of a pharmacological manipulation with an antipsychotic known to cause weight gain on metabolites, cognitive tasks and neural correlates related to food regulation. We used functional magnetic resonance imaging in conjunction with a task requiring visual processing of appetitive stimuli in schizophrenic patients and healthy controls before and after 16 weeks of antipsychotic medication with olanzapine. In patients, the psychological and neuronal changes associated following the treatment correlated with appetite control measures and metabolite levels in fasting blood samples. After 16 weeks of olanzapine treatment, the patients gained weight, increased their waist circumference, had fewer positive schizophrenia symptoms, a reduced ghrelin plasma concentration and an increased concentration of triglycerides, insulin and leptin. In premotor area, somatosensory cortices as well as bilaterally in the fusiform gyri, the olanzapine treatment increased the neural activity related to appetitive information in schizophrenic patients to similar levels relative to healthy individuals. However, a higher increase in sensitivity to appetitive stimuli after the treatment was observed in insular cortices, amygdala and cerebellum in schizophrenic patients as compared with healthy controls. Furthermore, these changes in neuronal activity correlated with changes in some metabolites and cognitive measurements related to appetite regulation.
... Taken together with past findings from the neuroimaging literature on the SN in both schizophrenia and eating disorders, our results suggest that enhancing the reactivity in the SN when people with AN engage in eating behaviour has the potential to be a treatment strategy. An important mechanism of action by which olanzapine and other second-generation APs may induce increases in appetite is the blockade of receptors, such as 5-hydroxytryptamine 2A , 5-hydroxytryptamine 2C serotoninergic; D 1 , D 2 , D 3 , and D 4 dopaminergic; and H 1 histaminergic, α1 and α2 adrenergic and cholinergic [25][26][27][28][29][30][31][32][33] -which are known to be involved in appetite regulation. Thus pharmacological modulation of insular reactivity through APs may increase sensitivity to food in patients with AN. ...
The salience network (SN), a set of brain regions composed of the anterior fronto-insular cortex (aFI) and the anterior cingulate cortex (ACC), is usually involved in interoception, self-regulating, and action selection. Accumulating evidence indicates that dysfunctions in this network are associated with various pathophysiological deficits in both schizophrenia and eating disorders, stemming mainly from dysfunctional information processing of internal or external stimuli. In addition, the metabolic side effects of some antipsychotics (APs), as well as their pharmacological mechanisms of action, also suggest a link between the functional and neurophysiological changes in the brain in both schizophrenia and in eating disorders. Nevertheless, there is still a knowledge gap in explicitly and directly linking the metabolic side effects associated with AP treatment with the dysfunction in SN associated with processing of food-related information in schizophrenia. Here we provide neuroimaging evidence for such a link, by presenting data on a group of schizophrenia patients who followed 16 weeks of olanzapine treatment and undertook a passive viewing task while their brain activity was recorded. In response to food-related dynamic stimuli (video clips), we observed a decreased activity in SN (aFI and ACC) after the treatment, which also correlated with ghrelin plasma concentration and a measure of dietary restraint. Taken together with past findings regarding the role of SN in both schizophrenia and eating disorders, our results suggest that enhancing the reactivity in the SN has the potential to be a treatment strategy in people with anorexia nervosa.
NCT 00290121.
The recent enthusiasm among clinicians for the so-called 'atypical antipsychotics' has both improved treatment for schizophrenic patients and provided a welcome stimulus for basic research on antipsychotic mechanisms. Even the newer drugs have shortcomings, and research is underway aimed at identifying novel agents with greater efficacy and safety. Much of this effort is directed towards compounds which, in addition to blocking dopamine receptors, also act on other neurotransmitter receptors such as 5-HT(2), 5-HT(1A) and alpha(2)-adrenergic receptors. However, there is also a large amount of scientific activity seeking to discover and develop selective dopamine receptor subtype antagonists (including compounds which specifically block D(3) or D(4) receptors) or drugs that specifically target the dopamine autoreceptor. Finally, a number of drug development programmes are searching for non-dopaminergic antipsychotics. Drugs that do not have affinity for dopamine receptors but act through neurotensin, sigma or cannabinoid CB, receptors or glutamatergic mechanisms are currently being evaluated. If any of these agents prove to have clinical efficacy this may lead to a third generation of antipsychotics. It is likely, however, that the mechanisms of action of such drugs will nevertheless imply the intimate involvement of dopaminergic pathways. (C) 2000 Lippincott Williams & Wilkins.
No effective treatment exists for the negative symptoms and cognitive impairments of schizophrenia. The loss of normal affective and cognitive function severely undermines a patients’ ability to regain independence and social reintegration even when the positive psychotic symptoms have been stabilized by medications that are currently available. The US Food and Drug Administration fully recognizes the need and legitimacy to target negative and cognitive symptoms in drug development. The theoretical consensus that the pathogenesis of these symptoms involves glutamatergic N-methyl-d-aspartate (NMDA) receptor hypofunction has been driving for over three decades the impetus behind the search for feasible pharmacological strategies to improve NMDA receptor function. One promising approach that emerged in recent years is up-regulating brain glycine levels through the blockade of glycine transporter 1 (GlyT1). It is hypothesized that increasing the availability of glycine, the obligatory NMDA receptor co-agonist, near glutamatergic synapses can boost NMDA receptor excitability without the risk of excitotoxicity following direct stimulation of NMDA receptor. This chapter traces the translation of glycine reuptake inhibition therapy through the latest Phase III clinical trials of the potent selective GlyT1 inhibitor, bitopertin, developed by F. Hoffman-La Roche. We will explore the relevant neural mechanisms underlying this new pharmacotherapy, which appears to possess board spectrum efficacy against both positive and negative schizophrenia symptoms. Preclinical evidence suggests that GlyT1 inhibition may modulate multiple neurotransmitter pathways, including mesolimbic dopamine and brain glycinergic inhibition, which may provide new leads for further target refinement.
For more than 40 years medication with neuroleptics has been the most important component in the treatment of schizophrenia, for both, symptom reduction as well as relapse prevention. Despite undeniable successes of the previous traditional antipsychotics these neuroleptics still are not very satisfactory with regard to nonresponse in positive symptoms, poor therapeutical outcome in negative symptoms and the frequent occurrence of undesirable extrapyramidal side-effects. With regard to these aspects and probably an increased compliance und higher quality of life, atypical neuroleptics should be more widely recognized.
Antipsychotic drugs (APDs) have proven their therapeutic worth for over four decades in the treatment of schizophrenia and a variety of other clinical conditions. As with any class of medications, APDs possess a wide range of side effect liabilities, varying greatly in regard to severity and incidence. These adverse side effects range from various forms of motor impairment to autonomic dysfunctions (Table 1). The side effects of APDs are deleterious not only for the suffering they produce in patients, but also for contributing to increased rates of noncompliance and relapse over the course of treatment. The relative likelihood of a particular side effect may be the ultimate deciding factor in choosing a specific drug. By gaining an understanding of side effect causes, treatment strategies can be pursued to lessen side effect problems. In addition, the ongoing development of novel APDs is largely guided by the need to improve side effect profiles. By identifying the role of various receptor subtypes in the etiology of adverse side effects, rational drug design can lead to improved pharmacotherapies. Indeed, the last 10 years have witnessed the introduction of several novel APDs which clearly show improved side effect profiles over earlier compounds.
Weight gain is a major side effect of antipsychotics (APs), which contributes to poor treatment adherence and significant morbidity. The mechanisms involved in AP-induced weight gain are incompletely understood. Recently, it has been proposed that changes in leptin, an cadipocyte-derived hormone exerting anorexigenic effects, may be involved in AP-induced weight gain. Thus far, studies on leptin changes during AP treatment have produced inconsistent results, prompting our group to perform a meta-analysis.
A search of the literature was performed using PubMed and Embase. Studies were included only if reporting peripheral levels of leptin before and after AP treatment in schizophrenia. Effect size estimates were calculated with Hedges g and were aggregated using a random effects model as results were heterogeneous (P < 0.10). Meta-regression analyses were performed using study length and changes in body mass index (BMI) as moderator variables.
Twenty-eight studies were retrieved, including 39 comparisons. A moderate and positive effect size was observed across studies. Olanzapine, clozapine, and quetiapine produced moderate leptin elevations, whereas haloperidol and risperidone were associated with small (nonsignificant) leptin changes. Across studies, BMI changes were significantly associated with increases in leptin levels. There was no effect of sex on AP-induced changes in leptin.
A physiological role of leptin in AP-induced weight gain is supported because the most significant leptin increases were observed with APs inducing the most weight gain and because of the observed association between leptin increases and BMI changes. The overall increase in leptin levels suggests that leptin acts as a negative feedback signal in the event of fat increase.
• Positron emission tomography and selective radioligands were used to determine D, and D2 dopamine receptor occupancy induced by neuroleptics in the basal ganglia of drug-treated schizophrenic patients. In 22 patients treated with conventional dosages of classical neuroleptics, the D2 occupancy was 70% to 89%. Patients with acute extrapyramidal syndromes had a higher D2 occupancy than those without side effects. This finding indicates that neurolepticinduced extrapyramidal syndromes are related to the degree of central D2 occupancy induced in the basal ganglia. In five patients treated with clozapine, the prototype atypical antipsychotic drug, a lower D2 occupancy of 38% to 63% was found. This finding demonstrates that clozapine is also "atypical" with respect to the central D2 occupancy in patients. During treatment with clozapine, there is a low frequency of extrapyramidal syndromes, which accordingly may reflect the comparatively low D2 occupancy induced by clinical doses of clozapine. Classical neuroleptics, like haloperidol or sulpiride, did not cause any evident D, occupancy, but the thioxanthene flupentixol induced a 36% to 44% occupancy. In four patients treated with clozapine, the D1 occupancy was 38% to 52%. The D, occupancy induced by clozapine and flupentixol may contribute to the antipsychotic effect of these drugs.
Positron emission tomography and selective radioligands were used to determine D1 and D2 dopamine receptor occupancy induced by neuroleptics in the basal ganglia of drug-treated schizophrenic patients. In 22 patients treated with conventional dosages of classical neuroleptics, the D2 occupancy was 70% to 89%. Patients with acute extrapyramidal syndromes had a higher D2 occupancy than those without side effects. This finding indicates that neuroleptic-induced extrapyramidal syndromes are related to the degree of central D2 occupancy induced in the basal ganglia. In five patients treated with clozapine, the prototype atypical antipsychotic drug, a lower D2 occupancy of 38% to 63% was found. This finding demonstrates that clozapine is also "atypical" with respect to the central D2 occupancy in patients. During treatment with clozapine, there is a low frequency of extrapyramidal syndromes, which accordingly may reflect the comparatively low D2 occupancy induced by clinical doses of clozapine. Classical neuroleptics, like haloperidol or sulpiride, did not cause any evident D1 occupancy, but the thioxanthene flupentixol induced a 36% to 44% occupancy. In four patients treated with clozapine, the D1 occupancy was 38% to 52%. The D1 occupancy induced by clozapine and flupentixol may contribute to the antipsychotic effect of these drugs.
In the present experiments, it was shown that the catalepsy induced by the dopamine D1 antagonist SCH 23390 (0.2 mg kg-1 sc), was completely antagonised by the administration of 8-OH-DPAT (0.1 mg kg-1 sc) for the duration of the effect of SCH 23390 (approx. 120 min). Neither the catalepsy induced by raclopride (16 mg kg-1 sc) nor that induced by SCH 23390 (0.2 mg kg-1 sc) could be antagonised by treatment with the 5-HT2 receptor antagonist ritanserin (0.13-2.0 mg kg-1 sc). Administration of SCH 23390 (0.0125-0.2 mg kg-1 sc) produced a significant suppression of avoidance behavior at all doses, and also produced a significant decrease in the number of intertrial crosses. At the higher doses, 0.05 and 0.2 mg kg-1 sc, there were also escape failures. In contrast to the finding in our previous report that raclopride and 8-OH-DPAT in a synergistic manner produce a suppression of conditioned avoidance behavior, no such interaction was found between 8-OH-DPAT (0.1 mg kg-1 sc) and SCH 23390 (6 micrograms kg-1 sc) in the present study.
The administration of the 5-HT1A agonist 8-OH-DPAT, 0.1 mg kg-1 sc-20 min, produced a moderate suppression of conditioned avoidance behavior (60% of controls) in the rat. This effect, however, was not seen after administration of higher doses, 0.4 and 1.6 mg kg-1 sc. The number of intertrial crosses were not affected by the lower dose but significantly increased by administration of the two higher doses of 8-OH-DPAT. The dopamine D2 receptor blocking agent raclopride, 0.05 mg kg-1, by itself did not suppress the avoidance behavior, but in combination with 8-OH-DPAT produced suppression of avoidance behavior (30% of controls) as well as intertrial crosses. Open field locomotor activity was suppressed by raclopride, 0.1 mg kg-1 sc, or by 8-OH-DPAT, 0.1 mg kg-1 sc. The combined treatment produced a further suppression of locomotor activity and a marked increase in "immobility" (stationary movements). Treadmill locomotion, however, was not affected by either compound by itself, whereas the combined treatment impaired treadmill performance. Suppression of treadmill performance by a higher dose of raclopride, 0.4 mg kg-1 sc, was not altered by the additional treatment with 8-OH-DPAT, 0.1 mg kg-1. In contrast to the additive effects of 8-OH-DPAT and raclopride on conditioned avoidance behavior, open field locomotion and treadmill performance, the catalepsy produced by raclopride, 16 mg kg-1 was completely antagonised by treatment with 8-OH-DPAT 0.1 mg kg-1. Taken together, the present findings demonstrate strong interactions between a 5-HT agonist and a DA D2 antagonist on some critical tests for antipsychotic-like actions and extrapyramidal motor effects in rats, and suggest new possibilities in the search for new antipsychotic drugs with higher clinical efficacy and less extrapyramidal side effects.
Four schizophrenic patients were investigated with dynamic positron emission tomography (PET) using (18F)fluorodeoxyglucose (FDG) and (18F)methylspiperone (MSP) as tracers. Two schizophrenics were on haloperidol therapy at the time of MSP PET. The other two schizophrenics were treated with clozapine, in one of them MSP PET was carried out twice with different daily doses (100 mg and 450 mg respectively). Neuroleptic serum levels were measured in all patients. Results were compared with MSP PET of two drug-free male control subjects and with a previous fluoroethylspiperone (FESP) study of normals. Three hours after tracer injection specific binding of MSP was observed in the striatum in all cases. The striatum to cerebellum ratio was used to estimate the degree of neuroleptic-caused striatal D2 dopamine receptor occupancy. In the haloperidol treated patients MSP binding was significantly decreased, whereas in the clozapine treated patients striatum to cerebellum ratio was normal. Even the increase of clozapine dose in the same patient had no influence on this ratio. Despite the smaller number of patients the study shows for the first time in humans that striatal MSP binding reflects the different D2 dopamine receptor affinities of clozapine and haloperidol.
The effect of various classes of serotonergic agents on haloperidol-induced catalepsy was evaluated in male Sprague-Dawley rats. The 5-HT-1A agonists buspirone, ipsapirone and 8-OH-DPAT all potently reversed catalepsy. The mixed 5-HT-1A and 5-HT-1B agonist RU 24969 reversed catalepsy only at the highest dose tested. The non-selective 5-HT-1 antagonist (l)-propranolol did not affect catalepsy. The 5-HT-2 agonist DOI and 5-HT-2 antagonist mesulergine both reversed catalepsy. ICS 205-930 (5-HT-3 antagonist) reversed catalepsy at low doses only. Another 5-HT-3 antagonist, GR 38032F, had no effect on catalepsy. These studies suggest that 5-HT-1A and 5-HT-2 receptor sites are important in the serotonergic modulation of haloperidol-induced catalepsy.
The selective serotonin1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) was studied for its ability to reverse haloperidol-induced catalepsy in rats. Given subcutaneously 8-OH-DPAT (0.06-0.5 mg/kg), dose-dependently antagonized the catalepsy induced by 1 mg/kg of haloperidol. Intraventricular injection of the serotonin (5-HT) neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), which caused marked depletion of 5-HT in brain, did not change haloperidol-induced catalepsy per se, but completely antagonized the anticataleptic effect of subcutaneously administered 8-OH-DPAT. When injected directly into the median or dorsal raphe nucleus, 8-OH-DPAT, in doses ranging from 0.2 to 5 micrograms/0.5 microliter, reduced the catalepsy induced by haloperidol. The results suggest that the activation of 5-HT1A receptors, probably those located presynaptically on 5-HT-containing cell bodies, reduces the catalepsy induced by haloperidol.
The influences of the indirect serotonin agonist fenfluramine (5; 10 mg/kg s.c.), the serotonin antagonist metergoline (5; 10 mg/kg s.c.) and the 5-HT1A agonist 8-OHDPAT (0.1; 0.2; 0.46 mg/kg s.c.) on haloperidol-induced catalepsy in rats or mice and on morphine-induced catalepsy in rats were studied. Morphine-induced catalepsy was enhanced by fenfluramine and attenuated by metergoline, whereas neither fenfluramine nor metergoline had any effect on haloperidol-induced catalepsy. 8-OHDPAT strongly antagonised catalepsy induced by morphine or haloperidol. We conclude that serotonergic transmission plays a major role in effectuating morphine catalepsy but not in effectuating haloperidol catalepsy. The antagonistic effect of 8-OHDPAT suggests a secondary, modulating role for 5-HT1A receptor mediated events in both types of catalepsy.